Increases in cholinergic system activity affect those with Parkinson-linked gene mutation

Hopeful mature couple.

A particular gene mutation associated with an inherited form of Parkinson’s disease (PD) offers new clues that call into question a controversial theory that changes associated with PD may begin in a different area of the brain. Idiopathic PD, a spontaneous form of the disease, affects the dopamine system and is treated with replacement therapy to restore the brain’s chemical balance and alleviate physical symptoms. Other neurotransmitter systems are often involved, but it is not clear whether this occurs prior to or after the dopamine loss characteristic of PD.  

By studying people with an inherited form of the disease, it is possible to assess brain involvement prior to the development of symptoms.

The results of an international collaboration led by Dr. Jon Stoessl, published today in The Lancet Neurology, show that mutations in LRRK2, a gene associated with an inherited form of PD, can cause imbalances in the cholinergic system of the brain – but not in the direction that researchers anticipated. The cholinergic system is responsible for learning and memory; cholinergic imbalances have been implicated in other neurodegenerative disorders, including Alzheimer’s disease.

While the investigators expected to find evidence of reduced cholinergic activity in the brain, positron emission tomography (PET) scans revealed widespread increases not only in people with the LRRK2 mutation-related form of PD, but also in unaffected individuals who carry the mutation but do not yet have manifestations of disease.

Changes in the cholinergic system are thought to contribute to PD complications including cognitive difficulties, postural instability and sleep disturbances.

“An increase in activity may reflect the brain’s attempt to compensate for dysfunction related to the mutated gene, and may also explain why  patients with LRRK2 mutations have fewer problems with certain complications of disease, even though their PD is in most ways similar to  the usual sporadic form of the disease,” said Dr. Jon Stoessl.

“The ability to study people with Parkinson-causing genetic mutations before they actually develop clinical evidence of disease provides a tremendous opportunity to test this hypothesis,” Dr. Stoessl explained.

The findings of this recent study have considerable implications for understanding how the disease begins to manifest in the years before diagnosis, and builds on research published last year that demonstrated that patients with the LRRK2 mutation show an increase in serotonin nerve terminals before a formal PD diagnosis, possibly reflecting the brain’s attempts to compensate for the decrease in dopamine associated with onset of physical symptoms.

According to Statistics Canada, PD is the second most common neurodegenerative disease in Canada, and more than 55,000 Canadians live with PD. It is a disease commonly associated with aging, and the majority of new diagnoses are in people older than 64 years. Symptoms of PD include stiffness, tremor, and poverty of movement in addition to behavioural and cognitive symptoms.

“It is gratifying to see this work come to fruition, given that we didn’t get funding from the Canadian Institutes of Health Research for this study, or the one before it,” said Dr. Stoessl. “In order to produce these findings, we had to look outside of Canada for the support to move forward.”

“While I am strongly supportive of the great urgency to fund basic science, it’s also true that clinical research is often overlooked by funding agencies,” explained Dr. Stoessl. “We need to invest in clinician-scientists, because without the financial support to pursue research it’s a very hard sell, especially for younger clinicians. Clinician-led research carries a lot of value, especially in terms of the translational research that directly benefits Canadians.”

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